Aromatic mercury amides and process of making the same



atented June 29, 1937 AROMATIC MERCURY AMIDES AND PROC- ESS OF MAKINGTHE SAME Carl N. Andersen, Wellesley Hills, Mass., assignor to LeverBrothers Company, a corporation of Maine No Drawing. Application April18, 1935, Serial No. 17,062

19 Claims.

The present invention relates to a method of producing certain neworganic mercury compounds, particularly organic mercury derivatives ofamides, and to the compounds produced thereby.

It is an object of my invention to produce new organic mercury compoundswhich may be regarded as derivatives of amides, and which are useful asgermicides and for other therapeutic l0 purposes.

The amide group is: CONH2. I have discovered that when one or both ofthe amido hydrogen atoms of an amide is replaced by the essentialradical of certain aromatic mercury compounds, compounds are producedwith extraordinarily high potency as antiseptics and germicides, and atthe same time are characterized by relatively low toxicity and otherdesirable properties.

The compounds I have produced may be described as having the generalformula (RHg) 131, in which R represents an aromatic structure, to acarbon atom of which the mercury is directly attached, in which a: is aninteger, usually 1, but

may be more if both of the amido hydrogens are replaced or if the amidecontains more than one amido group; and in which R1 is a radicalcorresponding to a compound having one or more amido groups. While theword group is used hereinafter, it is obvious that it is to beunderstood as plural where the value of a: is more than 1.

More particularly, R represents an aromatic structure, which may be anaromatic nucleus with or without side chains, and the expressionaromatic structure used herein, is intended to i be generic and includean aromatic nucleus with or without side chains. The aromatic structureis of the type in which none of the nuclear or side chain carbon atomshas direct linkage with any element other than hydrogen, carbon ormercury. B may stand for the phenyl group, CsHs, or for an aromatichydrocarbon having a nucleus similar to the phenyl hydrocarbons, as

for example, polycyclic hydrocarbons, in which all of the nuclear carbonatoms, other than the one attached to mercury, and any side chain carbonatoms, have their valences satisfied either by carbon or hydrogen.Examples are the di phenyl, tolyl, xylyl, and naphthylgroups.

The amines containing the -NH2 directly attached to a monovalentradical, do not react readily with aromatic mercury compounds to replacethe amino hydrogens. I have discovered,

however, due to the negative character of the carbonyl group, thehydrogen atoms of the amido group are more reactive and may be replacedwith aromatic mercury radicals.

The amides corresponding to the radical R1 may be either aliphatic oraromatic. Examples 5 of the aliphatic amides are: acetamide, sodiumamino succinamide (the amide of the sodium salt of asparagin), sodiumadipamide, palmitamide and cyanoacetamide. Examples of aromatic acidamides are: benzamidc, meta-sodium sulfonate 10 of benzamidc,salicylamide, ortho-sodium and ammonium sulfonates of benzamidc, andparanitrobenzamide. The above examples illustrate amides containing oneamido group, one or both of the hydrogens of which may be replaced by an15 aromatic mercury radical.

My invention includes aromatic mercury derivatives of amides containingmore than one amido group. Examples of these amides are: urea andoxamide. In these compounds the hydrogen or hydrogens of one or both ofthe amido groups may be replaced by an aromatic mercury radical.

Aromatic mercury derivatives of substituted amides are also includedwithin the scope of my invention. Examples of these amides are: Igepon T(oleic amido of ethane sodium sulfonate) and benzanilide.

The expression "amide as used herein is intended to include bothsubstituted and unsubstituted amides. 30

The general method of producing my novel compounds consists in reactingtogether the amide and a compound containing an aromatic mercury radicalof the above mentioned type. A common solvent for both the reactingcompo- 3r nents is employed. If the aromatic mercury compound formed isrelatively insoluble as compared with the reacting components, uponprecipitation it may be filtered, washed and dried.

If the compound is not insoluble, the reacting 0 mixture may beconcentrated by evaporation to precipitate the compound.

The aromatic mercury compound I prefer to use in reacting with the amideis the hydroxide. This has the advantage that water is the only 45 otherproduct of the reaction. The resulting compound, therefore, is easilypurified. I may also employ a soluble aromatic mercury salt, forexample, the acetate, or the lactate, in the reaction with the amide. Ingeneral, the aromatic 50 mercury amides produced are of relative lowsolubility as compared to the aromatic mercury salt, and are relativelyinsoluble as compared with the original amide.

The following examples are given as illustra- 5 tive of the processwhich is comprised in my invention and as illustrative of representativeorganic mercury derivatives of amides falling within the scope of myinvention.

Example 1 17.64 grams of phenylmercury hydroxide is dissolved in 1 liter'of water, and heated until solution is complete. The solution isfiltered to remove any insoluble material. To the filtrate is added 3.54grams of acetamide dissolved in 20' cc. of water. The solution remainsclear after mixing and is concentrated to one-half its volume, Uponcooling, crystals separate which are removed by filtration, washed wellwith water and then alcohol and dried. The material sinters at 100 C.,and has a melting point of 162 C.- It is the compound phenylmercuryacetamide.

Example 2 17.64 grams of phenylmercury hydroxide is dissolved in 1 literof water and heated until solution is complete. The heating is continueduntil the solution is concentrated to about 500 ccjand is then filtereddirectly into 200 cc. of alcohol containing 7.26 grams of benzamide. Awhite milky material separates and the reaction mixture is allowed tocool. The material is separated by filtration, washed well with waterand then a few cc. of alcohol, and. dried. It sinters at 165 C., and hasa melting point of 170.5 C. It is the compound phenylmercury benzamide.

Example. 3

. derivative of the sodium salt of amino succinamic acid. I

Example 4 20.64 grams of naphthylmercury hydroxide is dissolved in 1liter of water and heated until solution is complete. To the solution isadded 8.22 grams of salicylamide dissolved in 50 cc. of alcohol. Themixture is agitated and heated for a few minutes, after which it isfiltered while hot. On cooling well defined crystals precipitate, whichare separated by filtration, washed with alcohol and dried. The materialsi-nters at C., melts to an opaque liquid at 163164 C. and changes to aclear liquid at 169 C. It is the compound naphthylmercury salicylamide.

Example 5 35.28 grams of phenylmercury hydroxide is dissolved in 1 literof water and heated until solution is complete. Solution is filteredwhile hot to removed any insoluble material. is added 5.28 grams ofoxamide dissolved in 200 cc. of alcohol. A bulky white precipitate isformed and after the reaction mixture is allowed to cool the precipitateis separated by filtration, washed with water and a few cc. of alcoholand dried. The material decomposes sharply at To the filtrate.

267268 c. and is the compound diphenylmercury oxamide.

Example 6 phenylmercury benzanilide.

Example 7 17.64 grams ofphenylmercury hydroxide is dis-' solved in lliter of water and heated until solution is complete.. The solution isfiltered directly into 50000. of water in which has been dissolved 25.5grams of Igepon T '(oleic amide of ethane sodium sulfonate) A coarsematerial precipitates which is removed by filtration, washed well withalcohol and dried. The yield may be increased by concentrating thefiltrate on a steam bath after which additional precipitate is formedwhich is separated by filtration, washed with alcohol and dried. Thematerial sintersat 167 C., browns at 245 C., and does not melt up to 260C. It is the phenylmercury derivative of Igepon T.

From my investigation of compounds of this type I am led to believe thataromatic mercury derivatives corresponding to all of the amides may beprepared bymethods analogous to those described above. I thereforeintend my invention to be generic-and include the entire group.

From the specific examples it will be obvious to one skilled in the artwhat procedure is to be followed in producing these other compounds.Theoretical quantities of reacting materials are generally employed. Insome cases, if desired, approximately 10% excess of the amide may beused in order to insure complete conversion of the aromatic mercurycompound.

The operativeness of the process is not found to depend in anydeg'reeupon the temperature at which the reaction is effected. It isconvenient to use heat because it facilitates the solubility of thereacting components and speeds the reaction, but the process may becarried out at any temperature, for example, room temperature. If thereacting components are both water soluble, water is used as the solventfor reasons of convenience. The process, however, may be carried out inany solvent in which both the reacting components are soluble. Forexample, the alcohols or acetone, or mixtures of these with each otheror with water may be employed, depending on the solubility of thereacting components. In some instances the solvent employed willdetermine whether or not there will be water of crystallization in thefinal compound, but it will not otherwise affect the structure of thecompound.

All the compounds produced as above described are characterized byextraordinarily high potency as germicides. Tests to determine theefiicacy of some of them in killing B. typhosus and Staph. gureus werecarried on under the following condi- 1OI1S.

Aqueous solutions of varying dilutions from 1:10,000 upward untilkilling ceased, were made up.

These dilutions were employed in the conduct of tests according to thefollowing methods:

Circular 198, U. S. Dept. of Agriculture, Dec. 1931, described as F. D.A. method against Eberthclla typhz' (typhoid bacillus) at 37 C. and F.D. A. special method against Staph. aureus at As illustrative of thepotency of the compounds, the killing power of the following compoundsis given by way of example. The figures represent the maximum dilutionsat which killing in 15 minutes resulted:

Staph.

B. typhosus aureus Phenylmercury benzamide 1:60,000 1:20,000

Phenylmercury salicylamide- 1:50,000 1:20,000 Naphthylmercurysalicylamide 1:135,0Q0 1:20,000 Phenylmercury derivative of Igepon T1:80,000 1:40,000 Phenylmercury sodium metasulfo-benzamide 1:40,0001:20,000

In addition to their high germicidal value, all of these compounds arecharacterized by relatively low toxicity. Because of these properties itis possible to use them in extreme dilutions and in many situationswhere known germicides, because of toxic or other undesired properties,cannot be employed. They may be used externally and locally, and in somecases administered internally with satisfactory results from thegermicidal standpoint and without harmful effect to the body or itsfunctions.

The compounds retain their germicidal activity when incorporated in soapand various menstrums employed, in preparing germicidal compositions.

When these new compounds are to be used directly as germicides they maybe employed in aqueous or other solutions or they may be formed intovarious preparations such as mouth washes, tooth pastes, soaps,ointments, etc.

I claim:

1. The method of preparing aromatic mercury amides wherein an aromaticmercury group is linked to an amido group, which comprises reacting insolution an amide with an aromatic mercury compound of the kind whereinmercury is directly connected to a carbon atom of an aromatic structurein which none of the carbon atoms has direct linkage with any elementother than hydrogen, carbon and mercury, whereby the aromatic mercuryradical becomes attached to the amido group.

2. The method of preparing aromatic mercury amides wherein an aromaticmercury group is linked to an amido group, which comprises react ing insolution an amide with an aromatic mercury hydroxide of the kind whereinmercury is directly connected to a carbon atom of an aromatic structurein which none of the carbon atoms has direct linkage with any elementother than hydrogen, carbon and mercury, whereby the aromatic mercuryradical becomes attached to the amido group.

3. The method of preparing phenylmercury amides, which comprisesreacting in solution a compound containing an amido group with aphenylmercury compound.

4. The method of preparing phenylmercury amides wherein thephenylmercury group is linked to an amido group, which comprisesreacting in solution an amide with phenylmercury hydroxide.

5. A new aromatic mercury compound of the general formula (RHg).R1, inwhich R represents an aromatic structure to a carbon atom of which themercury is directly attached and in which none of the carbon atoms hasdirect linkage with any element other than hydrogen, carbon and mercury;in which R1 represents a radical containing an amido group that islinked to the RHg group through attachment to the nitrogen atom of theamido group and in which a: is an integer representing the number of RHggroups attached to the amide, which integer is at least one and not morethan twice the number of amido groups in the radical R1.

6. A new aromatic mercury compound of the general formula (RHg)=.R1, inwhich R represents an aromatic structure to a carbon atom of which themercury is directly attached and in which none of the carbon atoms hasdirect linkage with any element other than hydrogen, carbon and mercury;in which R1 represents a radical corresponding to an aliphatic amide,which radical is linked to the RHg group through attachment to thenitrogen atom of the amido group and in which a: is an integerrepresenting the number of RHg groups attached to the amide, whichinteger is at least one and not more than twice the number of amidogroups in the radical R1.

7. A new aromatic mercury compound of the general formula (RHg)1.R1, inwhich R represents an aromatic structure to a carbon atom of which themercury is directly attached and in which none of the carbon atoms hasdirect linkage with any element other than hydrogen, carbon and mercury;in which R1 represents a radical corresponding to an aliphatic amidecontaining two amido groups, which radical is linked to the RHg groupthrough attachment to the nitrogen atom of an amido group and in which1: is an integer representing the number of RHg groups attached to theamide, which integer is at least one and not more than twice the numberof amido groups in the radical R1.

8. A new aromatic mercury compound of the general formula (RHghRi, inwhich R represents an aromatic structure to a carbon atom of which themercury is directly attached and in which none of the carbon atoms hasdirect linkage with any element other than hydrogen, carbon and mercury;in which R1 represents a radical corresponding to an aromatic amide,which radical is linked to the RHg group through attachment to thenitrogen atom of the amido group and in which :c is an integerrepresenting the number of RHg groups attached to the amide, whichinteger is at least one and not more than twice the number of amidogroups in the radical R1.

9. A new aromatic mercury compound of the general formula (RHg):.R1, inwhich R represents an aromatic structure to a carbon atom of which themercury is directly attached and in which none of the carbon atoms hasdirect linkage with any element other than hydrogen, carbon and mercury;in which R1 represents a radical corresponding to an aromatic amidehaving one amido group, which radical is linked to the RHg group throughattachment to the nitrogen atom of the amido group and in which :n is aninteger representing the number of'RHg groups attached to the amide,which integer is at least one and not more than twice the number ofamido groups in the radical R1.

10. A new aromatic mercury compound of the general formula (RI-Ig)=.R1,in which R repre- 15 general formula. (CsHaHg) .R1,

general formula sents an aromatic structure to a carbon atom of whichthe mercury is directly attached and in which none of the carbon atomshas direct linkage with any element other than hydrogen, carcon andmercury; in which R1 represents a radical containing a substituted amidogroup, which radical is linked to the RHg group through attachment tothe nitrogen atom of the substituted amido group and in which :1: is aninteger l representing the number of RHg groups attached to the amide,which integer is at least one and not more than twice the number ofamido groups in the radical R1.

11. A new aromatic mercury compound of the in which R1 represents aradical containing an amido group that is linked to the CaHaHg groupthrough attachment to the nitrogen atom of the amido group and in whicha: is an integer representing a number of CeHsHg groups attached to theamide, which integer is at least one and not more than twice the numberof amido groups in the radical R1.

12. A new aromatic mercury compound of the 25 general formula(CaH5Hg).R1, in which R1 represents a radical corresponding to analiphatic amide, which radical is linked to the CeHsHg group throughattachment to the nitrogen atom of the amido group and in which a: is aninteger 30 representing a number of CsI-IsI-Ig groups attached to theamide, which integer is at least one and not more than twice the numberof amido groups in the radical R1.

13. A new aromatic mercury compound of the (CeHsHghRu, in which R1represents a radical corresponding to an aliphatic amide containing twoamido groups, which radical is linked to the CsHsHg group throughattachment to the nitrogen atom of an amido group and 0 in which a: isan integer representing a number of CsHsHg groups attached to the amide,which integer is at least one and not more than twice the number ofamido groups in the radical R1. 14. A new aromatic mercury compound ofthe 5 general formula (CsHsHghaRi, in which R1 represents a radicalcorresponding to an arcmatic amide, which radical is linked to theCeHeHg group through attachment to the nitrogen atom of the amido groupand in which :0 is an integer representing a number of CeHeHg groupsattached to the amide, which integer is at least one and not more thantwice the number of amido groups in the radical R1.

15. A new aromatic mercury compound of the general formula(C8H5Hg):c.R1, in which R1 represents a radical corresponding to anaromatic amide having one amido group, which radical is linked to theCaHaHg group through attachment to the nitrogen atom oi the amido groupand in which a: is an integer representing a number of CeHtHg groupsattached to the amide, which integer is atleast one and not more thantwice the number of amido groups in the radical R1.

16. A new aromatic mercury compound of the general formula(CeI-I5Hg).R1, in which R1 represents a radical containing a substitutedamido group that is linked to the CeHeHg group through attachment to thenitrogen atom of the substituted amido group and in which .1: is aninteger representing a number of CsHsHg groups attached to the amide,which integer is at least one and not more than twice the number ofamido groups in the radical R1.

17. A new aromatic mercury compound ofthe general formula (C6H5Hg).r-R1,in which R1 represents the radical of salicylamide, to the amidonitrogen of which the CsHsHg group is attached; and in which a: is aninteger representing one of the numbers 1 and 2.

18. A new aromatic mercury compound of the general formula (CeHsHgmRr,in which R1 represents the radical of oxamide, to which the CGHSHggroups are linked through attachment to amido nitrogen.

19. A new aromatic mercury compound of the general formula CsHsHg.R1, inwhich R1 represents the radical of oleic amide of ethane sodiumsulfonate, to the amido nitrogen of which the CeHsHg group is attached.

CARL N. ANDERSEN.

